Abstract
Resveratrol, a trans-stilbene polyphenolic compound and its synthetic analogs are widely used bioactive molecules due to their remarkable chemo-preventive potential. Here, we have identified a novel synthetic trans-stilbene compound, Z-DAN-11 ((Z)-3-(3, 4-dimethoxyphenyl)-2-(3, 4, 5-trimethoxyphenyl) acrylonitrile) which shows remarkable efficacy in blocking tumor growth and progression both in vitro and in vivo. Z-DAN-11 inhibits proliferation of cancer cells in vitro through microtubule depolymerization that induced G2/M arrest and consequently leads to apoptotic cell death. More importantly, Z-DAN-11 shows limited cytotoxicity to normal cells as compared to cancer cells. Quite interestingly, we have found that Z-DAN-11-mediated ROS production helps in dramatic alteration in the mitochondrial redox status which critically contributes to the apoptosis. Mechanistic studies reveal that Z-DAN-11 induces the expression of pro-apoptotic proteins and decreases anti-apoptotic protein expression that decisively helps in the activation of caspase 8, caspase 9, and caspase 3, leading to cleavage of PARP1 and cell death via intrinsic and extrinsic pathways of apoptosis. Moreover, Z-DAN-11-mediated apoptosis of cancer cells is through a partial p53-dependent pathway, since both HCT116 p53−/− cells as well as p53-silenced cells (siRNA) were able to block apoptosis partially but significantly. Importantly, Z-DAN-11 also imparts its anti-tumorigenic effect by inhibiting clonogenic property and anchorage-independent growth potential of cancer cells at concentrations at least 10 times lower than that required for inducing apoptosis. Finally, in vivo study with immuno-competent syngeneic mice shows Z-DAN-11 to be able to impede tumor progression without any adverse side-effects. Hence, we identified a novel, synthetic trans-stilbene derivative with anti-tumorigenic potential which might tremendously help in devising potential therapeutic strategy against cancer.
Highlights
Among the various interventions used therapeutically against cancer, chemotherapy along with radiotherapy has Official journal of the Cell Death Differentiation AssociationParida et al Cell Death and Disease (2018)9:448 collateral damages to normal cells
The series of compounds (Z-DAN-1 to Z-DAN-22) shown in Fig. S1 were assessed for their ability to block proliferation of HeLa, MCF-7, and NKE cells
The anti-proliferative efficacies of the tested compounds in terms of IC50 were presented in Table S1, which showed three compounds Z-DAN-10, ZDAN-11, and Z-DAN-12 to possess higher efficacy in inhibiting proliferation of HeLa as well as MCF-7 cells compared to the other derivatives
Summary
Among the various interventions used therapeutically against cancer, chemotherapy along with radiotherapy has Official journal of the Cell Death Differentiation AssociationParida et al Cell Death and Disease (2018)9:448 collateral damages to normal cells. Several methoxy and hydroxy derivatives of trans-stilbene have shown to possess anticancer activity in various human cancer cells through growth suppression by inducing cell cycle arrest and apoptosis[11,12,13]. The need to identify potential leads that can block cancer progression through targeted blocking of cells in particular phase of cell cycle[14]. We synthesized a number of trans-stilbene derivatives in an attempt to identify potential anti-cancer leads which is able to deliver a multi-modal yet targeted anti-cancer therapy, through affecting some of the key cellular processes primarily involved in carcinogenesis. We evaluated the anticancer potential of 22 synthetic trans-stilbene derivatives using several cancer cell lines and identified one lead, Z-DAN-11 ((Z)-3-(3, 4-dimethoxyphenyl)-2-(3, 4, 5-trimethoxyphenyl) acrylonitrile), based on its ability to inhibit proliferation of cancer cells but not normal cells. Trans-stilbene derivative, Z-DAN-11 holds tremendous potential as an ideal lead towards targeted cancer chemotherapy, which either alone or in combination with existing chemotherapy may be used as a potential strategy towards cancer treatment
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